The epidermal growth factor receptor (EGFR) may play a key role in initiating the pathogenic effects of the fibrogenic and carcinogenic mineral fiber, asbestos, through modulation of the mitogen-activated protein kinase (MAPK) cascade. In pleural mesothelial cells, crocidolite asbestos activates extracellular signal-regulated protein kinases (ERK1/2) through a mechanism involving EGFR phosphorylation that is linked to expression of the c-fos protooncogene and apoptosis. This proposal further explores MAPK pathway modulation by asbestos, focusing on the possibility that asbestos-induced cell proliferation also is coupled to the EGFR through a signal transduction pathway linked to ERK5, another ERK/MAPK family member. ERK5 has been linked to expression of the c-fos and c-jun early response genes and recently was shown to be part of a distinct MAPK signaling pathway required for EGF-induced cell proliferation and progression through the cell cycle. The overall hypothesis is to be tested in this proposal is that asbestos initiates activation of ERK/MAPK signaling pathways through an EGFR-dependent mechanism that is causally related to cell proliferation and cell cycle alterations via the ERK5 pathway. Studies will be performed in alveolar type II epithelial cells, a critical early target cell of asbestos-induced disease. Alveolar type II epithelial cell proliferation initially following asbestos exposure may be crucial to repair and regeneration. Dysregulated proliferation is pathogenic and may underlie asbestos-induced pulmonary fibrosis and lung cancer.